Diabetes mellitus is the most common of the serious metabolic diseases affecting humans. It has been estimated that there are over 200 million diabetics in the world. (See J. Steinke and J. S. Soeldner, Diabetes Mellitus in Principles of Internal Medicine, 8th ed., 563 (1977). Diabetics not only face a decreased life expectancy but also the ever-present possibility of disabling complications.
Metabolically, diabetes is characterized by an inappropriate elevation of blood glucose levels. In type I Diabetes Mellitus, this is due to an absence of insulin in the individual. In type II Diabetes Mellitus, although there is circulating insulin, its signal is not efficiently transduced via the insulin receptor, giving rise to insulin resistance, where the body responds less and less well to a given amount of insulin. Insulin is a peptide hormone which is produced by the Langerhans islets in the pancreas. Insulin triggers increased glucose utilization, protein synthesis, and the formation and storage of neutral lipids. The present invention focuses on Type II diabetes mellitus or non-insulin-dependent diabetes.
Diabetes mellitus is also characterized by long term complications involving the eyes, nerves, kidneys, and blood vessels. These diabetic complications include premature atherosclerosis, intercapillary glomerulosclerosis, retinopathy, and neuropathy. The major cause of morbidity and mortality among diabetics is coronary heart disease. M. J. Garcia, McNamara, P. M., Gordon, T., Kannell, W. E., Diabetes 34:105-111 (1974).
The increased blood glucose levels are associated with altered lipid and protein metabolism. Increased serum glucose concentrations leads to an increase in non-enzymatic glycation of various proteins, such as hemoglobin in erythrocytes and albumin in the serum. Non-enzymatic glycation of proteins can affect the normal activity in the body. For instance, Cu, Zn-superoxide dismutase, which traps superoxide radicals, is inactivated by glycation reaction. Glycation-induced changes in the activities of body proteins has been postulated to be a contributor to the pathology of diabetes. Brownlee, "Glycosylation Products as Toxic Mediators of Diabetic Complications" Annu. Rev. Med. 42:159-66 (1991).
The primary goal in treatment of all types of diabetes is to maintain blood glucose levels as close to normal as possible. For type II diabetes, the first line of therapy for maintaining blood glucose levels is modification of diet and lifestyle. The diabetic diet features restrictions on fat content and an increased intake of dietary fiber. Regular exercise is also emphasized to decrease weight and reduce the degree of insulin resistance.
If diet and lifestyle modifications fail to control glucose levels, a trial of either oral hypoglycemic therapy or insulin therapy is required to control glucose levels and thus minimize complications related to the disease.
Type II diabetics who cannot control their blood glucose levels through diet and exercise may respond to sulfonylurea drugs (e.g. glibenclamide). See Bailey, C. J., "The Problem of Insulin Resistance", The Genetic Engineer and Biotechnologist, Biopaper No. 12.5.53 (1992). These drugs act primarily by increasing the level of insulin production from the remaining active pancreatic beta cells. However, these compounds may have serious complications. For example, sulfonylureas may lead to dangerous hypoglycemic reactions including coma. Furthermore, these compounds may not be used in diabetic patients with hepatic or renal insufficiency. Sulfonylureas also produce gastrointestinal side effects which are not well tolerated by many of the patients. See Jackson, R. A., et al., Diabetes, 36:632-40 (1987). As the disease progresses, the conditions of a substantial number of patients worsen to the point where oral agents cannot adequately control blood glucose levels and insulin therapy becomes necessary. Gray, H., and O'Rahilly, S., Archives of Internal Medicine, 155: 1137 (1995). Other compounds used to treat diabetes such as, biguanide and metformin also have serious drawbacks.
Although advances in treating diabetes have greatly extended the lives of diabetics, they still cannot expect a normal life expectancy. Furthermore, diabetics must suffer the long term degradative effects of diabetes, including blindness, renal insufficiency, heart disease, and gangrene of the feet. New methods are needed to increase glycemic control, in order to lessen the adverse effects of diabetes.
Since the pioneering work by Houssay (B. A. Houssay, A. Biasotti, E. Di Benedetto, and C. T. Rietti, Compt. R. Soc. Biol. Paris 112:494 (1932)), many studies have documented a strong connection between growth hormone ("GH") and glycemia, with hypoglycemia acting to increase GH levels (J. Roth, S. H Glick, R. S. Yallow, and S. A. Berson, Science 140:987 (1963)) and GH acting to cause insulin resistance (N. Venkatesan, et al., "Insulin Resistance in Rats Harboring Growth Hormone-secreting Tumors: Decreased Receptor Number but Increased Kinase Activity in Liver," Metab. Clin. Exp. 44:75-84 (1995)) and hyperglycemia (M. Press, et al., "Effect of Insulin on Growth Hormone-Induced Metabolic Derangement in Diabetes," Metab. Clin. Exp. 35:956-59 (1986). As reviewed by Sonksen et al. (P. H. Sonksen, D. Russell-Jones, and R. H. Jones, Horm. Res. 40:68 (1993)), high levels of GH are diabetogenic, and the lowering of GH by hypophysectomy often improves the control of diabetes mellitus, and can halt the progression of retinopathy. Unfortunately, the physiological rationale for these effects of GH, and the molecular mechanism by which GH modulates blood glucose levels have not been elucidated.
U.S. Pat. No. 5,350,836 to Kopichick et al. discloses treating diabetes patients with antagonists of growth hormone. Similarly, U.S. Pat. No. 4,505,897 to Coy, et al., identified a relationship between somatostatin antagonists and increased levels of growth hormone and insulin. However, growth hormone is not able to antagonize successfully the action of insulin in the first 120 minutes. P. De Feo et al., Am. J. Phys. 256:E835 (1989), B. R. Pal, P. E. Phillips, D. R. Mathews, and D. B. Dunger, Diabetologia 35:542 (1992).
The possibility that GH effects are mediated by a natural insulin antagonist found in the human plasma (L. Vargas, et al., Biochem. J. 77:43 (1960); K. W. Taylor, L. Vargas, and P. J. Randle, Lancet 1:1313 (1960)), which is induced by administration of GH (L. Vargas, M. Bronfman, and M. E. Kawada, Horm. Metab. Res. 6:275 (1974)), have been pursued for many years. Insulin antagonism induced by growth hormone was believed to be associated with a glycoprotein (L. Vargas, et al., Excerpta Med. Internat. Congress. Series 209, Abstract 82 (1970)) found in the .alpha.2-globulin fraction of normal plasma. This fraction has been referred to as the .alpha.2-inhibitor or .alpha.2-glycoprotein (.alpha.2-GP). .alpha.2-GP appears to be produced by the liver about 2 hours after exogenous treatment with GH, or after endogenous stimulation of GH by stress and chlorpromazine, or by insulin-induced hypoglycemia. L. Vargas and M. E. Kawada, Horm. Metab. Res. 8:383 (1976); L. Vargas and M. E. Kawada, Horm. Metab. Res. 17:259 (1985); L. Vargas, et al., Arch. Biol. Med. Exper. 6:54 (1969). Clinical observations demonstrate that both the production and action of .alpha.2-GP are independent of the adrenal gland. L. Vargas and M. E. Kawada, Horm. Metab. Res. 8:383 (1976). In hypophysectomized patients or patients with panhypopituitarism, plasma insulin activity is normal whereas .alpha.2-GP activity is not detectable by in vitro assays, but it reappears after GH administration. K. W. Taylor, L. Vargas, and P. J. Randle, Lancet 1:1313 (1960). On the other hand, in one patient with an excess of GH (acromegaly), high levels of .alpha.2-GP activity are present, and, after hypophysectomy, the activity of .alpha.2-GP disappears and insulin reappears. K. W. Taylor, L. Vargas, and P. J. Randle, Lancet 1:1313 (1960).
Although, .alpha.2-GP has been identified as an insulin antagonist, its identity and characteristics have not been determined. The present invention is directed to advancing beyond this state of the art.